The translational goal of this project is to conduct mechanistic studies on BRAFmut mCRC patients and patient derived xenografts of BRAFmut mCRC treated with dual BRAF and EGFR inhibition to understand predictive biomarkers and mechanism on resistance through 1) a phase I/Ib trial of vemurafenib, cetuximab and irinotecan 2) a national SWOG randomized phase II trial of the combination. 3) concurrent patient derived xenografts trials. The hypothesis to be tested in this proposal is that the combination of BRAF and EGFR inhibition will prove efficacious in BRAFV600E colorectal cancer, but that innate and adaptive resistance mechanisms exist; biomarkers and parallel preclinical efforts are needed to better characterize these mechanisms of resistance. This hypothesis will be tested in vitro, in vivo, and in patients with mCRC in a clinical trial. Three specific aims are proposed to test this hypothesis, and include: 1) determine the safety and efficacy of BRAF and EGFR inhibition in patients with mCRC in a phase I/Ib trial and a national phase II randomized trial; 2) use patient-derived specimens to define predictive biomarkers and mechanisms of innate resistance to BRAF and EGFR inhibition; 3) use co-clinical trials with BRAFmut patient-derived xenografts to identify and target mechanisms of acquired resistance. The long-term goal of this project is to develop an understanding of the mechanisms of resistance to therapy for BRAFmut mCRC so that we can design more effective therapies, identify new drug targets for treatment, and develop biomarkers that identify BRAFmut mCRC patients most likely to have responses to specific therapies. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page